GADD153 mediates celecoxib-induced apoptosis in cervical cancer cells$
1 Cancer Research Institute, Seoul National University College of Medicine 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea
2 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea
3 Department of Obstetrics and Gynecology, Seoul National University College of Medicine 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, Korea
4 Molecular Therapy Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, South Korea
*To whom correspondence should be addressed. Tel: +82 2 2072 2822; Fax: +82 2 3668 7401; Email: yssong{at}snu.ac.kr
Abstract
Celecoxib, a selective cyclooxygenase 2 inhibitor, is known to have anti-inflammatory activity and to induce apoptosis in various types of cancer cells. Here, we examined the molecular mechanism of celecoxib-induced apoptosis in cervical cancer cell lines (HeLa, CaSki and C33A). Screening of a microarray cDNA-chip containing 225 different genes revealed that growth arrest and DNA damage inducible gene (GADD153), a transcription factor involved in apoptosis, showed the strongest differential expression following celecoxib treatment in all three cervical cancer cell lines. Notably, siRNA-induced silencing of GADD153 suppressed celecoxib-induced apoptosis in all the three cell lines, and exogenous expression of GADD153 triggered apoptosis in cervical cancer cells in the absence of other apoptotic stimuli. A luciferase reporter gene assay and mRNA stability tests revealed that expression of GADD153 was regulated at both the transcriptional and post-transcriptional levels following celecoxib treatment. The region between –649 and –249, containing an intact C/EBP-ATF binding site, was required for the basal activity and celecoxib-induced stimulation of GADD153 promoter activity. Also, mRNA stability test showed that celecoxib prolonged the half-life of GADD153 mRNA. In terms of signaling pathway, addition of the NF-
B inhibitor, N-tosyl-L phenylalanyl-chloromethyl ketone (TPCK), had no effect on GADD153 expression levels. Celecoxib treatment induced Bak expression, whereas cell treated with siGADD153 or TPCK showed lower levels of celecoxib-induced Bak up-regulation. These novel findings collectively suggest that GADD153 may play a key role in celecoxib-induced apoptosis in cervical cancer cells by regulating the expression of proapoptotic proteins such as Bak.
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